The prevalent approach to preparing vaccines for viruses with seasonal or year-to-year patterns is modeled by commercial Influenza vaccines which require the anticipation, publication, and subsequent synthesis of a new vaccine when the virus evolves to present a different antigenic profile. This approach causes significant timeline delays and cost as new antigens are synthesized in anticipation of the next years viral strain. Further, as evidenced by the failings of the 2008 influenza vaccine, errors in the predicted strain can result in significant disease related costs as patients are under-protected. Thus, improved methods for designing and preparing vaccines to protect against multiple circulating strains of disease-causing virus is desirable.
Noroviruses are non-cultivatable human Caliciviruses that have emerged as the single most important cause of epidemic outbreaks of nonbacterial gastroenteritis (Glass et al. (2000) J Infect Dis, Vol. 181 (Sup 2): S254-S261; Hardy et al. (1999) Clin Lab Med, Vol. 19(3): 675-90). These viruses have been grouped into five different genogroups of which genogroups I and II are further subdivided into greater than 25 genotypes and are the agents for the vast majority of illness in humans attributed to this virus. There are significant challenges to the development of vaccines against Norovirus, including the inability to propagate the virus in culture and suitable animal models of acute gastroenteritis. Standard virologic techniques including viral attenuation or in vitro neutralization assays are therefore not possible today.
Noroviruses contain a 7.5 Kb single strand positive sense RNA genome that contains three open reading frames. The major viral capsid protein (VP1) is encoded by ORF2 and expression of this protein results in the spontaneous assembly of virus-like particles (VLPs), which mimic the structure of the virus but are incapable of replication. This structure is composed of 180 monomeric subunits of VP1 and are candidate vaccines to prevent acute gastroenteritis. The VP1 monomer has two domains: a shell (S) domain that forms the inner viral core and a prominent protruding (P) domain linked by a flexible hinge. The P domain is further subdivided into two subdomains P1 and P2, which is the most surface exposed region and is thought to contain important cell recognition and antigenic sites. Homology analysis indicates that the majority of the hypervariable amino acid regions of VP1 are located in the P2 domain (Allen et al. (2008) PLoS One, Vol. 1:1-9).
Recent epidemiology studies have lead to the hypothesis that Norovirus evolution is epochal with periods of stasis followed by emergence of novel epidemic strains, similar to that observed for Influenza virus. Most recent outbreaks appear to be related to emergence of variant virus in the GII.4 genotype at a persistence interval of around two years. There is a need in the art for a vaccine candidate that provides antigenic epitopes that would be cross protective for multiple Norovirus, or other non-enveloped virus strains, which would obviate the need for construction of vaccines for each contemporary outbreak strain.